Challenges in the field of oncology include the lack of efficient means for early cancer detection and for specific cancer subtyping. There is a need for new cancer diagnostics that can provide early and specific diagnosis of cancer and enable targeted therapy and prognosis. The need for new diagnostics has been the impetus behind many initiatives targeting the discovery and development of new serum biomarkers for cancer. The hope is that the identification of suitable biomarkers will allow for the development of early cancer detection screening tests and will lead to improved cancer therapy and a reduction in the mortality associated with many cancers.
Alpha-Fetoprotein (AFP is included in the recommended list of biomarkers outlined by the National Academy of Clinical Biochemistry (NACB) in their Practice Guidelines and Recommendations For Use Of Tumor Markers In The Clinic, Liver Cancer (Section 3D) (Lamerz et al., National Academy of Clinical Biochemistry Guidelines for the Use of Tumor Markers in Primary Liver Cancer). The serum concentration of AFP in normal adults is, typically, less than 10 ng/mL. Serum AFP levels above 10 ng/mL may be indicative of cancer or chronic liver diseases, including hepatitis and liver cirrhosis. Levels greater than 400 to 500 ng/mL are considered indicative of human hepatocellular carcinoma (HCC) and may be used to discriminate HCC from chronic benign conditions, particularly if there is a sustained increase in AFP levels over time. However, not all hepatocellular carcinomas secrete AFP (e.g., the Fibrolamellar type do not). Still further, AFP could be elevated in pregnancy, in patients with other tumors of gonadal origin and in some patients with acute or chronic viral hepatitis without a tumor.
CA 125 is a serum biomarker associated primarily with epithelial ovarian cancer. While CA 125 levels are often elevated in liver cancer, it reportedly lacks specificity for HCC, as CA125 levels may also become elevated due to benign liver conditions, the presence of ascites or surgery (Bergmann et al. 1987; Collazos et al. 1992; Devarbhavi et al. 2002; Haglun et al. 1991; Kadayifci et al. 1996, 1997; Elias and Kew 1990; Miralles et al. 2003; Molina et al. 1991; Xiao and Liu, 2003).
CEA and CA 19-9 are serum biomarkers that are most commonly linked with colorectal cancer (CEA) and pancreatic and biliary tract cancer (CA 19-9). Previous studies have not found CEA or CA 19-9 to be significant biomarkers for liver cancer (Fabris et al. 1991; Leandro et al. 1989; Lopez et al. 1997; Maestranzi et al. 1998). There are studies suggesting use of CEA and CA 19-9 as tumor markers of the metastasis of colorectal cancer to the liver (Ishizuka et al. 2001; Lorenz et al. 1989).
Therefore, while the use of AFP as a biomarker for HCC has been documented, the value of CA 125, CEA and CA 19-9, alone or in combination with AFP, has not been recognized in the art. Moreover, the elevation of CEA, CA 19-9, OPN, MMP-9, E-cadherin, and erbB2 in patients with cirrhosis and/or HCC has not been observed to date.